Current Vascular Pharmacology - Volume 13, Issue 5, 2015

Percutaneous coronary intervention is widely used to reduce the risk of death or cardiovascular events in patients with acute coronary syndromes. Dual antiplatelet treatment with aspirin and clopidogrel has become routine practice to prevent thrombotic events after coronary surgery. Despite advances of significant reduction of thrombotic complications in this adjunctive therapy, major adverse cardiovascular events still occur, suggesting the need for development of novel antiplatelet agents that act as superior alternatives to current standard regimen. Recently developed antiplatelet agents (prasugrel, ticagrelor, cangrelor and elinogrel) efficiently antagonize P2Y12 receptor, a key platelet activating signaling pathway, and thereby inhibit aggregation induced by mediators such as ADP, collagen, thrombin and TXA2. We provide an evidence-based review on the pharmacological and clinical performance of clopidogrel and novel antiplatelet agents that antagonize P2Y12 receptors.

Glycaemic management is of paramount importance in the cardiac surgery setting. A growing body of evidence confirms a J-shaped relationship between blood glucose (BG) level and perioperative morbidity and mortality. On one hand, acute hypoglycaemia causes irreversible cerebral damage. On the other hand, hyperglycaemia increases the risk of infections, acute kidney injury, atrial fibrillation, low cardiac output syndrome, cerebrovascular accidents and cognitive impairment. Also, high BG variability, even within the therapeutic window, may deteriorate the outcome. Therefore, moderate perioperative insulin management is usually recommended, with target BG adjusted to individual needs and possibilities. Continuous BG monitoring is a promising tool that should help practitioners in everyday decision-making process of glycaemic control. This review summarises the current evidence-based knowledge on the perioperative management of hyperglycaemia.

Accumulation of lipids in the intima is the initial and crucial step in atherogenesis, but, this step is not always synonymous with atherogenesis. The factors that trigger the mechanisms modulating lipid accumulation in the vessel wall and in the subsequent development of atherosclerotic plaque remain unclear. In this review we evaluate whether atherogenesis is modulated by cortisol, the end hormone of the stress-related anti-inflammatory system. The amount of accumulated lipids in the intima depends on the balance between the penetration and efflux of cholesterol from the artery wall. We assess whether cortisol is involved in this balance. Cortisol can increase the penetration of lipids, and, simultaneously, might reduce their efflux from the intima. We also report a critical analysis on whether atherogenesis, which has a local nature, can be modulated by a systemic factor. In addition, we comment on the synergistic action of cortisol with insulin in atherogenesis, and consider relevant recent clinical evidence regarding the role of cortisol in atherosclerosis. Glucocorticoids, by triggering the mechanisms that favor the penetration of lipids in the intima, and modulating factors that control the efflux of cholesterol from the artery wall, may lead to the formation of atherosclerotic plaques. Thus, cortisol may have a role in atherogenesis. This may have important clinical, therapeutic and preventive implications.

There has been a considerable effort to improve adjunctive antithrombotic therapies to reperfusion strategies in the treatment of ST-segment elevation Myocardial Infarction (STEMI). Therefore, the aim of this article is to provide a critical and updated overview of recent advances on adjunctive antithrombotic therapies in patients undergoing primary angioplasty for STEMI. Due to very low costs, early Unfractionated Heparin (UFH) plus additional periprocedural administration should still be regarded as the gold standard in antithrombotic therapy, whereas subsequent subcutaneous administration of Low Molecular Weight Heparins (LMWHs) or fondaparinux should be considered, especially in patients at higher risk of thromboembolic complications. Periprocedural bivalirudin should be considered instead of a strategy of combined UFH and Glycoprotein (Gp) IIb/IIIa inhibitors, especially among patients at higher risk of bleeding complications. New oral ADP antagonists should be administrated as early as possible soon after diagnosis, whereas the use of clopidogrel should be limited to the cases when the new ADP antagonists are not available or contraindicated. However, rivaroxaban has obtained indication for Acute Coronary Syndromes (ACS), and therefore its combination with aspirin and clopidogrel will gain recognition especially among STSegment Elevation Myocardial Infarction (STEMI) patients. Future trials are needed to compare different possible strategies with oral antithrombotic therapies and in particular optimal duration, especially in the era of new DES that have been shown to reduce the risk of stent thrombosis. Early Gp IIb/IIIa inhibitor use may be considered as upstream therapy especially in high-risk patients, whereas the choice of periprocedural administration may be based on thrombus burden or in case of impaired haemodynamic conditions that may compromise oral drug absorption. Overall, a more aggressive antithrombotic approach should be considered within the first hours from symptom onset, when the considerable viability justifies aggressiveness. The use of radial approach and potential protamine administration should be considered in order to minimize the risk of bleeding complications. Due to the very low mortality currently achieved by primary angioplasty and stenting, a further reduction in short or mediumterm mortality would be not easy to demonstrate. Therefore, additional endpoints, such as infarct size and myocardial perfusion, may be considered in future randomized trials especially for the evaluation of new periprocedural antithrombotic therapies among patients undergoing mechanical revascularization for STEMI.

Pharmacogenetics investigates heritable genetic polymorphisms that can effect responses to drug therapy. The main application of pharmacogenetics is genotype-guided dosing of medications and genotype-selection of treatment with the highest efficacy and lowest risk of adverse effects. Cardiovascular disease (CVD) is the leading cause of mortality and morbidity globally. Dyslipidemia is one of the classical risk factors for developing CVD. 3-hydroxy-3-methylglutaryl-coenzyme (HMGCoA) reductase inhibitors called statins are the cornerstones in dyslipidemia treatment. However, there is a broad variation in individual responses to statin treatment. This variation may not only be due to environmental factors such as adherence to treatment, diet and exercise but also due to genetic factors. Many studies have focused on various genetic polymorphisms of genes that are involved in cholesterol metabolism, trying to define their contribution to a potential genotype-guided treatment against dyslipidemia.

Background: Diabetes mellitus (DM) remains a health care challenge worldwide. We evaluated the trends and outcome of DM in patients presenting with cardiovascular diseases (CVD) over a 22-year period in Qatar. Methods and Results: A retrospective analysis was performed between 1991 and 2012, including 48,803 patients admitted to the tertiary Heart Hospital (HH). The average CVD hospitalization rate was 37 admissions per 10,000 people, of which, 2 out of 5 patients had DM. Diabetic males were 6 years younger than females. DM was more prevalent in Arabs (68 vs. 32%), but its burden showed a decreasing trend over time compared with South Asians. More diabetics presented with ST-elevation myocardial infarction (47.5 vs. 22.7%), which tended to occur 8 years earlier compared with heart failure. Over the study period, beta-blocker use increased substantially (from 10 to 71%). However, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) were underutilized (from 30 to 56%). There were 4.4 deaths per 100 CVD admissions, which is equivalent to 97 deaths per year. Of this, 52% had DM (2.3 deaths per 100 CVD admissions). The overall case fatality rate (CFR) of DM was 5.6%. Diabetic Asian patients died 9 years earlier than diabetic Arabs at the HH. Multivariate regression analysis revealed that predictors of mortality in DM patients in the HH included lack of beta-blocker use (OR 4.35; 95% CI: 0.20 – 0.27), lack of ACEI/ARBs use (OR 3.58; 95% CI: 0.23 – 0.32), myocardial infarction (OR 3.20; 95% CI: 2.77 – 3.68), lack of aspirin use (OR 2.56; 95% CI: 0.34 – 0.45), congestive heart failure (OR 1.75; 95% CI: 1.50 – 2.04) and age (OR 1.03; 95% CI: 1.02 – 1.04) (P=0.001 for all). Conclusion: DM remains a healthcare challenge in Qatar. Although the admission rate of diabetic patients is increasing at the HH, the mortality rate is decreasing. The use of evidence-based medication is still far from the guideline recommendation; however, it has substantially improved. The lack of evidence-based CVD medications in diabetic patients was associated with an increased mortality up to 4-fold in the HH. Moreover, there is a need to enhance public awareness regarding CVD risk factors and DM through education programs for the adoption of healthier lifestyles and nutrition. Great efforts are needed for more efficient primary and secondary prevention strategies in diabetic patients.

With a history that began in 800 A.D., coffee is the most popular drink known and as a result, the issues regarding its physiologic effects deserve attention. Maintaining alertness is a wellknown benefit and in addition, the cardiovascular (CV) effects of the active compounds, which include polyphenols and caffeine, must be considered. Genetics are relevant and where slow caffeine metabolism is inherent, the risk of nonfatal myocardial (MI) has been shown to be increased. Overall risk for coronary heart disease (CHD) is not supported and unless there is excessive intake, congestive heart failure (CHF) is not adversely affected; in moderation, there may be some benefit for CHF. There is no apparent increased risk of sudden cardiac death (SCD). Overall, there also appears to be a beneficial inverse association with all-cause mortality, although this is not absolute for extra heavy intake. Benefit in reducing stroke also has supportive evidence. Hypertension is not increased by coffee. Boiled and unfiltered coffee appears to increase plasma cholesterol and triglycerides but for the overall metabolic syndrome, there appears to be benefit. There is also some evidence that paper-filtered coffee results in an increase in some markers of inflammation. Association of coffee with arrhythmias has been a major concern though in moderation it is not a significant overall problem. Therefore, only if a patient were to associate major arrhythmic symptoms with coffee would cessation have to be advised. Where coffee clearly shines from a CV standpoint is in the established decrease in onset of type 2 diabetes mellitus (DM). Any benefit or harm has always been attributed to caffeine as the apparent major component. However, coffee contains a myriad of compounds, including polyphenols. These other substances may be most relevant for potential benefit or harm and some of these may be partially removed or altered by coffee preparation methods such as paper filtration. Multiple studies support this by what appears to be no CV advantage or disadvantage for decaffeinated coffee. The bottom line on coffee, for those who enjoy the brew, is that it is a wonderful beverage with rare associated CV disadvantage and with much to recommend it from an overall CV standpoint.

Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and is more prevalent in patients with type 2 diabetes mellitus (T2DM). Incretin-based antidiabetic agents (glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors) are used in the treatment of T2DM but it is unclear whether they may also play a role in the management of NAFLD. We systematically reviewed the PubMed and Scopus database up to October 2014 and also hand-searched the references of the retrieved articles for studies evaluating the effects of these agents on NAFLD. In animal studies, both GLP-1 receptor agonists and DPP-4 inhibitors reduced transaminase activity and steatosis but their effects on liver inflammation were inconsistent and fibrosis was not assessed. In clinical studies, both agents consistently reduced transaminase activity and steatosis as assessed non-invasively. There are very limited data on the effects of incretin-based treatments on liver histology. In conclusion, GLP-1 receptor agonists and DPP-4 inhibitors appear to hold promise in patients with NAFLD but larger controlled studies with histological and clinical endpoints are needed to evaluate their effects in this population.

Cardiovascular disease (CVD) is among the most major causes of morbidity and mortality worldwide. Great progress has been made in the management of CVD which has been influenced by the use of experimental animal models. These models provided information at cellular and molecular levels and allowed the development of treatment strategies. CVD models have been developed in many species, including large animals (e.g. pigs and dogs) and small animals (e.g. rats and mice). Although, no model can solely reproduce clinical HF, simulations of heart failure (HF) are available to experimentally tackle certain queries not easily resolved in humans. Induced HF may also be produced experimentally through myocardial infarction (MI), pressure loading, or volume loading. Volume loading is useful to look at hormone and electrolyte disturbances, while pressure loading models is helpful to study ventricular hypertrophy, cellular imbalance and vascular changes in HF. Coronary heart disease is assessed in MI animal models. In this review we describe various experimental models used to study the pathophysiology of HF.

Background: The number of human immunodeficiency virus (HIV)-infected patients has increased significantly, although the number of deaths due to HIV and acquired immunodeficiency syndrome (AIDS) has dramatically reduced. Highly active antiretroviral therapy (HAART) has increased not only survival but also the risk of deaths caused by other diseases or by long-term side effects of these drugs. AIM: The aim of this study is to evaluate the nephrotoxicity of one of the most common anti-retroviral drugs, tenofovir disoproxil fumarate (TDF). Materials and Methods: We examined 27 patients with HIV infection (10 women). Patients assumed TDF for a mean period of 8.03 months. Indexes of renal function and serum electrolytes were measured, and glomerular filtration rate was estimated (eGFR). Proteinuria, glycosuria, bicarbonaturia, and phosphaturia were assessed, and renal ultrasound examination was carried out. Results: Acute kidney injury with glycosuria, bicarbonaturia, and phosphaturia was seen in 22 patients. Substantial recovery of renal function occurred in 19 patients. Conclusion: This study highlights that TDF nephrotoxicity is a widely frequent but reversible form of renal damage with preferentially proximal tubular dysfunction. We suggest that all patients at the time of HIV diagnosis should carry out a screening for kidney disease with eGFR assessment, proteinuria, and urine analysis.

Background and Aims: Recent findings have highlighted enhanced fish consumption as a potential measure to increase intake of healthy fatty acids, particularly omega-3. The generalizability of this recommendation, however, may fall short of differences in fish species and cooking techniques. Hence, we investigated how these 2 variables affect the lipid content in fish flesh. Methods and Results: Nine species of freshwater, deep sea or shore fish were grilled, steamed or fried with or without the addition of soybean oil, olive oil or butter. The lipid composition was analysed and a significant difference was observed in cholesterol, saturated fatty acids, polyunsaturated fatty acids, omega-3 fatty acids and omega-6 fatty acids contents between species (p<0.05). The use of soybean or olive oil was associated with a significant change in flesh concentration of polyunsaturated, omega-3 and omega-6 fatty acids (p<0.05). Conclusion: This study calls attention to the specific lipid content that must be expected from different fish species and cooking techniques.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) contributes significantly to the pathogenesis of atherosclerosis. MiR-10b has recently emerged as a critical mediator in regulating cell proliferation in many diseases. In our study, miR-10b expression was up-regulated in VSMCs isolated from atherosclerotic plaques, as well as in PDGFstimulated VSMCs.Overexpression of miR-10b promoted cell proliferation of VSMCs. Furthermore, we identified the Tat-interacting protein 30 (TIP30) as a direct target gene of miR-10b. TIP30 was down-regulated in VSMCs isolated from atherosclerosis plaques, as well as in proliferative VSMCs. Knockdown of TIP30 promoted VSMCs proliferation. In addition, miR-10b induced TIP30 down-regulation was accompanied by increased Akt phosphorylation. Akt was critical for miR-10b-mediated VSMCs proliferation. Our results demonstrated that miR-10b contributed to abnormal VSMCs proliferation through inhibiting the Akt pathway by targeting TIP30 in atherosclerosis. The modulation of miR-10b in VSMCs provides a potential target for the therapy of atherosclerosis.

We aimed to determine the association between the change in mean platelet volume (MPV) over time and aspirin/ clopidogrel resistance in patients undergoing percutaneous coronary intervention (PCI). The MPV and platelet function were analysed in 302 patients who underwent PCI. MPV changes were associated with increased aspirin reaction units (ARU, r = 0.114; P = 0.047), increased P2Y12 reaction units (PRU, r = 0.193; P = 0.001), and decreased P2Y12% inhibition (PI%, r = - 0.273; P < 0.001). The group with increasing MPV values showed significantly higher PRU values and lower PI% compared with the group with decreasing MPV values (222.5 ± 73.9 vs. 195.6 ± 63.7 PRU, P = 0.001; 24.1 ± 21.0 vs. 32.8 ± 18.5 PI%, P < 0.001, respectively). The clopidogrel resistant group (≥235 PRU or ≤15% of PI%) showed a significantly higher positive change in MPV (ΔMPV) values than the clopidogrel responder group (0.53 ± 0.78 vs. 0.13 ± 0.69 fL, P < 0.001). When the ΔMPV cut-off level was set at 0.20 fL using the receiver operating characteristic curve, the sensitivity and specificity for differentiating between the clopidogrel resistant and responder groups were 72.6% and 59.3%, respectively. After adjusting for traditional risk factors, the odds ratio in the clopidogrel resistant group with ΔMPV ≥0.2 fL was 4.10 (95% confidence interval; 1.84-9.17). In conclusion, ΔMPV was associated with PRU and PI%; a positive ΔMPV was an independent predictive marker for clopidogrel resistance after PCI.